The COVID-19 pandemic: European regulators respond

Monia Tumminello

Manager, Cortellis Regulatory Intelligence

Clarivate

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The COVID-19 pandemic is spreading around the world with, as of this writing, more than one million cases globally and more than 500,000 cases in Europe alone. Here we summarize how The European Medicines Agency (EMA) as well as the European Commission (EC), the Heads of Medicines Agency (HMA) and the European Center for Disease Prevention and Control (ECDC) are responding to this unprecedented health crisis.

The importance of cooperation

As the European Commission said “…the evolution of the COVID-19 pandemic is affecting countries with different levels of severity at varying times. Many patients are in need of highly specialized care. The practical experience on how to manage patients, in particular severe cases, is scarce and scattered in Europe. While the experience and the number of cases treated by some hospitals is important, others are only starting to deal with complex patients. The concrete techniques and treatments applied to the COVID-19 patients are in many cases experimental and there are some limitations to access the newly acquired knowledge from these past weeks and months.”

For this reason, the European Commission (EC) launched the “COVID-19 Clinical Management Support System1” with the objective to support clinicians in hospitals that are currently facing the coronavirus emergency all over Europe. This initiative will help to create rapid connections among the hospitals indicated by the Member States as reference centers for COVID-19. This synergy aims to speed up the adoption of specific treatment options and help reduce some of the uncertainties due to the unknown aspects of the virus.

ENCePP and EMA strongly encourage all researchers to register their pharmaco-epidemiological studies related to the COVID-19 pandemic in the EU PAS Register. Researchers are also encouraged to upload and make public the study protocol, with a description of the data collected or planned to be collected, in order to facilitate and speed-up the design of observational studies by others.

On top of that, the Joint Research Centre (JRC) of the EC has designed a new control material that laboratories can use to check the correct functioning of their coronavirus tests and to avoid false negatives. A recent EU survey identified the lack of positive control materials as one of the top three challenges faced by laboratories for the reliable implementation of coronavirus tests. Responding to this need, JRC scientists have designed a positive control material to facilitate the quality control of the detection of SARS-CoV-2 in testing laboratories. The new control material has the potential to improve the EU’s capacity to respond to the virus outbreak and avoid valuable resources being wasted by inefficient tests. In the Information Note2 published by the EC, information is provided related to 3,000 samples ready to be dispatched to the testing laboratories across the EU, including the major reference virology centers as well as hospitals. Thus the 3,000 samples that are now ready make it possible to check up to 60 million tests throughout the EU.

The Joint Research Centre (JRC) of the EC has designed a new control material that can be used to avoid false negatives in coronavirus tests. Three thousand samples are now ready and can check 60 million tests in the EU.

Social media vs. Official media

EMA published a press release3 giving advice to continue using medicines for hypertension, heart or kidney disease during the COVID-19 pandemic in response to recent media reports and publications stating that some medicines, e.g., angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs, or sartan medicines), could worsen coronavirus disease (COVID-19). EMA confirmed that the speculation around the fact that ACE-inhibitors or ARBs treatment can make infections worse in the context of COVID-19 is not supported by clinical evidence. However, EMA is monitoring the situation closely and collaborating with stakeholders to coordinate epidemiological studies on the effects of ACE inhibitors and ARBs in people with COVID-19.

EMA also published a press release4 on the use of non-steroidal anti-inflammatories for COVID-19 in response to questions raised about whether the use on non-steroidal anti-inflammatory medicines (NSAIDs) such as ibuprofen could worsen coronavirus disease. EMA confirmed that there is currently no scientific evidence establishing a link between ibuprofen and worsening of COVID.

In this press release EMA explained that in May 2019, EMA’s safety committee (PRAC) started a review of the non-steroidal anti-inflammatory medicines ibuprofen and ketoprofen following a survey by the French National Agency for Medicines and Health Products Safety (ANSM) which suggested that infection due to chickenpox (varicella) and some bacterial infections could be made worse by these medicines. The product information of many NSAIDs already contains warnings that their anti-inflammatory effects may hide the symptoms of a worsening infection. The PRAC is reviewing all available data to see if any additional measure is required.

Electronic certificate: Temporary or definitive decision?

An EMA Press Release5 explains how the Agency will no longer provide printed certificates; only electronically signed and authenticated certificates will be printed to maintain EMA’s ability to provide these documents during the COVID-19 pandemic. The new format of the certificates is based on an electronically signed PDF document. It contains an electronic signature fully compliant with the eIDAS Regulation (Regulation (EU) No 910/2014) that guarantees the unique link to the signatory and the full authenticity and integrity of the document. The new format will apply to all ongoing and future requests. The Agency will consider whether the electronic signature should be implemented as a permanent solution as part of its efforts to digitalize its administrative processes for all documents requiring signature.

Medical equipment

As of today, the European Commission is making available guidelines to assist manufacturers in ramping up production of masks and other personal protective equipment (PPE) and 3D printing in the context of the coronavirus outbreak. Regarding the first topic, the European Commission issued a question and answer document6 to respond to manufacturers’ questions on protective equipment production. This guideline helps manufacturers to assess the applicable legal and technical requirements before importing new products to the EU, launching new or reconverting existing facilities to produce protective equipment like masks, gloves and surgical gowns.

The other guidance7 is on conformity assessment procedures for 3D printing and 3D printed products for medical use in the context of the coronavirus outbreak. The document aims to detail the applicable EU legal frameworks for those products and sets out examples of technical standards which manufacturers may use in order to place compliant products on the EU market.

As the guidance explained, 3D Printing (3DP) is a manufacturing process that uses 3D Printers, also known as Additive Manufacturing machinery, to fabricate other market products. 3D printers are among the so-called ‘harmonized products’ for which there is specific EU product harmonization legislation in place. In particular, they fall under the definition of machinery under the Machinery Directive 2006/42/EC. Besides, the Machinery Directive, other EU pieces of legislation may apply to 3D printers; i.e. the Electromagnetic Compatibility Directive 2014/30/EC, and EU legislation on chemicals, WEEE 2012/19/EU, RoHS II 2011/65/EU Directive and Directive (EU) 2017/2102, and REACH 1907/2006/EU. 3D printed products in themselves may be used to produce medical devices that fall within the scope of specific EU product legislation, such as the Medical Devices Directive 93/42/EEC. Depending on the intended purpose of the 3D printed product, they may qualify as medical devices, or accessories according to the definitions set out in the medical device legislation.

A further communication8 comes from the European Committee for Standardization (CEN) and the European Committee for Electrotechnical Standardization (CENELEC) that, in collaboration with all their members, have agreed to immediately make available a number of European standards for certain medical devices and personal protective equipment. This action will help both EU and third-country companies willing to manufacture these items to quickly start production and place products on the international market more easily while ensuring a high degree of safety.

A Recommendation9 of the European Commission on conformity assessment and market surveillance procedures within the context of the COVID-19 threat was published. The objective is to ensure availability of personal protective equipment (PPE) and medical devices for adequate protection in the COVID-19 outbreak. The Commission invites all economic operators throughout the supply chain, as well as notified bodies and market surveillance authorities, to deploy all the measures at their disposal to support the efforts aimed at ensuring that the supply of PPE and medical devices throughout the EU market will match the continuously increasing demand. Such measures should ensure that any PPE or medical device, which is being placed on the EU market, continues to provide an adequate level of protection of users’ health and safety.

Vaccines

EMA published a press release10 providing an update on treatment and vaccines under development in Europe, confirming that at this stage, based on the preliminary data presented to the Agency, no medicine has yet demonstrated efficacy in treating COVID-19.

EMA’s COVID-19 response team has been in contact with developers of approximately 40 therapeutic medicines. Potential treatments for COVID-19 that are undergoing the clinical trials to assess their safety and efficacy against the disease include:

remdesivir (investigational)

lopinavir/ritonavir (currently authorized as an anti-HIV medicine)

chloroquine and hydrox

hychloroquine (currently authorized at a national level as treatments against malaria and certain autoimmune diseases such as rheumatoid arthritis)

systemic interferons and in particular, interferon beta (currently authorized to treat diseases such as multiple sclerosis)

monoclonal antibodies with activity against components of the immune system

As noted in the press release, EMA has also had discussions with developers of a dozen potential COVID-19 vaccines, two of which have already entered phase I clinical trials. EMA estimates that it might take at least one year before a vaccine against COVID-19 is ready for approval and available in sufficient quantities to enable widespread use.

EMA also confirmed that it has a range of support measures that can help to facilitate and speed up the development of medicines, which in addition to fast-track scientific advice includes the PRIME scheme, the accelerated assessment, and conditional marketing authorization procedures.

It is also important to highlight the decision taken by the EMA Executive Director to reduce, for one year, the scientific advice fees by 100% on products for the prevention and/or treatment of COVID-19.

The EMA Executive Director has called for free scientific advice fees on products that could prevent and/or treat COVID-19.

Managing clinical trials during COVID-19 pandemic

The European Commission, the European Medicines Agency (EMA) and national Head of Medicines Agencies (HMA) published the Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic.11 Various challenges exist that result in restrictions of visits to healthcare facilities, increased demands on the health service and changes to trial staff availability. Participants may also be required to self-isolate, which introduces difficulties for investigators to maintain medical oversight. These challenges could impact trial conduct, such as completion of trial assessments, completion of trial visits and the provision of Investigational Medicinal Products (IMPs).

As stated in the Guidance, the sponsor should consider changes in the ongoing trials, such as conversion of physical visits into phone or video visits, suspending or slowing down the recruitment of new trial participants or the extension of the duration of a trial. Changes to informed consent are also reported, as it should be taken into account the cases where potential COVID-19 trial participants lack capacity to consent due to severity conditions or due to isolation for COVID-19 positive infection. Other changes could affect the distribution of the IMP, with the removal of visits to sites and providing trial participants with needed treatments.

Such measures raise various practical considerations, including whether the IMP is appropriate for administration and general storage at the trial participant’s home, how the product stability will be maintained during transit, how safe custody of the product will be ensured and how IMP accountability and the evaluation of treatment compliance will be managed. Changes to monitoring and auditing are also listed as well as the management of safety report, risk assessment and communication with Authority.

EMA’s Human Medicines Committee (CHMP) has published a statement12 urging the EU research community to prioritize large randomized controlled studies because they are most likely to generate the conclusive evidence needed to enable rapid development and approval of potential treatments of COVID-19. The statement promotes a harmonized approach to data collection and a robust methodology for COVID-19 clinical trials across the EU to make best use of the available supply of investigational agents. It emphasizes the need to include all EU countries in these trials.

The ECDC (European Centre for Disease Prevention and Control) published a Guidance Document13 on COVID-19 and Substances of Human Origin that aims to provide a risk assessment and management options for the safe and sustainable supply of substances of human origin (SoHO). As the guidance says, although SARS-CoV-2 virus is transmitted from human to human via droplets, uncertainties about the presence of the virus in the blood and bodily fluids of an asymptomatic SoHO donor may be considered a potential threat to the viral safety of SoHO. This guidance analyzes the risks posed by COVID-19 to transplant recipients, to the sufficiency and sustainability of SoHO supply and consider precautionary actions to mitigate the microbial safety of SoHO.

As the European Commission clarified, the Substances of Human Origin are considered to be essential goods/services for which free circulation within the EU is crucial.

Protection of personal data in the fight against COVID-19

The European Data Protection Board (EDPB) released a statement14 on the processing of personal data in the context of the COVID-19 outbreak. Governments, public and private organizations throughout Europe are taking measures to contain and mitigate COVID-19 that can involve the processing of different types of personal data. Even in these exceptional times, the data controller and processor must ensure the protection of the personal data of the data subjects.

The most discussed topic in these difficult days is the use of mobile location data. This document answered the following question: “Can Member State governments use personal data related to individuals’ mobile phones in their efforts to monitor, contain or mitigate the spread of COVID-19?” In some Member States, governments envisage using the mobile location data, possibly allowing the geolocation of individuals or to send them health messages in a specific area by phone or text message, as a possible way to monitor, contain or mitigate the spread of COVID-19. Personal data protection rules do not apply to data that has been appropriately anonymized. When it is not possible to only process anonymous data, the ePrivacy Directive enables Member States to introduce legislative measures to safeguard public security. The proportionality principle also applies.

The EDPB confirmed that the GDPR (General Data Protection Regulation) is a broad piece of legislation and provides for rules that also apply to the processing of personal data in a context such as the one relating to COVID-19. The GDPR allows competent public health authorities and employers to process personal data in the context of an epidemic, in accordance with national law and within the conditions set therein.

Looking ahead

Covid-19 is a rapidly evolving situation, and all European Regulatory Authorities have a great challenge to overcome. Responses should be coordinated, rapid and in collaboration with all the European Institutions and Member States. We can’t fight this pandemic alone.